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Title: Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment
Author: Martínez González, Loreto
Rodríguez Cueto, Carmen
Cabezudo, Diego
Bartolomé, Fernando
Andrés Benito, Pol
Ferrer, Isidro (Ferrer Abizanda)
Gil, Carmen
Martín Requero, Ángeles
Fernández Ruiz, Javier
Martínez, Ana
Lago, Eva de
Keywords: Esclerosi lateral amiotròfica
Proteïnes quinases
Amyotrophic lateral sclerosis
Protein kinases
Issue Date: 10-Mar-2020
Publisher: Nature Publishing Group
Abstract: athogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1δ inhibitor IGS-2.7, both in a TDP-43 (A315T) transgenic mouse and in a human cell-based model of ALS, is shown. Treatment with IGS-2.7 produces a significant preservation of motor neurons in the anterior horn at lumbar level, a decrease in both astroglial and microglial reactivity in this area, and in TDP-43 phosphorylation in spinal cord samples. Furthermore, the recovery of TDP-43 homeostasis (phosphorylation and localization) in a human-based cell model from ALS patients after treatment with IGS-2.7 is also reported. Moreover, we have shown a trend to increase in CK-1δ mRNA in spinal cord and significantly in frontal cortex of sALS cases. All these data show for the first time the in vivo modulation of TDP-43 toxicity by CK-1δ inhibition with IGS-2.7, which may explain the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1δ inhibitors in a future disease-modifying treatment for ALS.
Note: Reproducció del document publicat a:
It is part of: Scientific Reports, 2020, vol. 10, p. 4449
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ISSN: 2045-2322
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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